The use of radiotherapy is quite common in modern medicine. Radiotherapy is used for a variety of uses, such as for post-surgery treatment of tumors, for various types of cancer therapy and, lately, the art has found that radiotherapy can be useful in preventing restenosis in patients treated for coronary diseases. Restenosis has been treated so far by short-term irradiation with radioactive sources located in catheters and wires, and by long-term irradiation with implanted devices, such as stents.
Many different radioactive materials have been used, including xcex2 and xcex3-emitters. In typical devices employed in the art, a radioactive portion is provided in a device to be inserted in a body cavity, in a variety of ways. In one method, the radioactive material is generated separately from the device, and attached thereto in a variety of ways, such-as by containerization, coating, etc., and in other methods the device, e.g., a catheter, is irradiated shortly before use, to generate the radioactive material to be used for the treatment, and the device is then inserted into the body cavity.
The production of Rhenium188 (Re188) from Tungsten188 (W188) for pharmaceutical uses is described, e.g., in U.S. Pat. No. 5,382,388, U.S. Pat. No. 5,186,913, U.S. Pat. No. 5,145,636 and U.S. Pat. No. 4,778,672. According to the prior art Re188 is generated in aqueous solution, and it must then be separated from the reagent, W188, and complexed to organic and biological complexes prior to its injection into the body. Also, the prior art describes the use of tungsten oxide, where the tungsten is enriched W186. Also large reaction volumes are described. The above chemistry limits the use of the product only to solutions and excludes the potential to apply it as a wire or coil for medical applications. The present invention describes the use of natural tungsten in a metal form. This configuration allows production of radioactive tungsten coil which generates in situ radioactive rhenium without the need to separate between the tungsten and the rhenium.
Another method of producing Re188 is via the neutron activation of Re187. However, purified Re188 has a half life of about 17 hours, which is a very low shelf life for medical purposes. This means that, according to the prior art, in order to be able to use Re188 in therapy, irradiation of the device must take place shortly before the surgical procedure takes place, which requires suitable and complex logistics for the hospital.
The present invention exploits the production of W188 and its decay to Re188, which are as follows: 
The half-life time (txc2xd) of W188 is 69 days and Os188 is stable. W188 is prepared by a double neutron activation of W186 target. The tungsten target is made from natural tungsten which has an abundance of 28.6% W186 (xe2x80x9cTable of Isotopes,xe2x80x9d Lederer, Hollander and Perlman, John Wiley and Sons.)
The advantages of using xcex2-emitting sources are known in the art. Particularly, xcex2-emitting sources have a limited depth of penetration in tissue and are therefore particularly suited for treatments, such as the prevention of restenosis, which do not require in-depth penetration and in which, in fact, in-depth penetration is undesirable. The xcex2-emission of R188 is suitable for penetration depth of 4-5 mm, in tissue, and the xcex3 photons emission can be used to image the source within the body cavity. Furthermore, tungsten and rhenium have been used in medicine according to the known art, and no undesirable toxic effects have been disclosed to date (for toxicity see xe2x80x9cThe Merck Index,xe2x80x9d 1968, 8th Ed., p. 916).
Another important advantage of tungsten and rhenium is their high atomic number, which makes them excellent x-ray radio opaque markers. This feature is important for catheterization procedures and, even more, for non-opaque stents positioning within a vessel. Furthermore, in case of break or leak of part of the source, this x-ray contrast property enables the clinician to monitor its location and to attempt to retrieve it.
So far, however, the art has failed to provide a radioactive source which is convenient to use, which does not require expensive and hazardous irradiation procedures on the spot, and which provide the desired major proportion of xcex2-emission, with only minor amount of y-emission. Furthermore, the art has so far failed to provide such a source which, in addition to the above-mentioned desirable properties, is also relatively long-lived.
It is an object of the present, invention to provide a radioactive source for therapy, which overcomes the above-mentioned drawbacks of prior art sources.
It is another object of the invention to provide medical devices utilizing the source of the invention, which can be utilized in a variety of radiotherapy procedures, and particularly for the treatment and/or the prevention of restenosis.
It is a further object of the present invention to provide a long life Re188 radioactive therapeutic device.
It is a still further object of the present invention to provide a method for the manufacture of a Re188 radioactive therapeutic device that is free from the need to purify and to complex Re188 prior to use.
It is a still further object of the present invention to provide a novel method of practicing radiotherapy by the use of Rhenium188 as the source of radioactivity.
Other objects and advantages of the invention will become apparent as the description proceeds.
According to the present invention, W188 is used in in situ generation of Re188 for the purpose of radioactive therapy. Thus, the present invention provides a therapeutic device comprising a radioactive W188/Re188 source.
Preferably, the material of said source is tungsten metal. The source is. made of said material of coated with said material.
Preferably, the therapeutic device is coil-shaped and has a main body made of, or coated or implanted with, tungsten. In a preferred embodiment, it comprises a source wire having a W188/Re188 source at its distal tip. Also preferably, said radioactive source has a volume of not more than about 0.850 ml.
Preferably, said source wire is in the form of any of the group which consists of, but is not limited to, catheters, guidewires, stents or implants (pellet). Optionally, said source wire is made of tungsten or made of other suitable matter and coated with tungsten.
Preferably, the length of said source wire is between 1-50 mm, more preferably between 25-50 mm, and its diameter is between 0.2-10 mm, more preferably between 0.34-5 mm.
More preferably, when utilized in high xe2x80x9cdose-ratexe2x80x9d catheters, said source is 25-42 mm long, its diameter being between 0.34-0-8 mm; when utilized in stents, the source is 10-30 mm long, with a diameter of 0.7-3 mm, when utilized as interstitial implants the source is about 3-10 mm long with a diameter of about 0.3-1 mm, and when utilized as a round shape source, its diameter is about 3-10 mm. A xe2x80x9chigh dose-rate sourcexe2x80x9d is defined as a source that can irradiate the target organ and achieve the desired dose in several minutes. Illustrative and non-limitative examples of suitable doses are those comprised between 1,500-5,000 rad; the activity is typically up to 100 mC, W188 and the irradiation time is up to 30 minutes, more preferably up to 7 minutes.
Preferably, the W/Re source is within the activity range of 0.25 microcuries to 200 millicuries of W188/Re188.
In a preferred embodiment of the invention, the therapeutic device consists of or comprises a radioactive source consisting in a hollow coil made of Tungsten188 wire, with wall thickness of not less than 75 pm. It has been found that this coil wall thickness enables complete self-absorption of the undesired Tungsten isotopes, e.g., W188 and W185 and complete in situ separation between Tungsten and the desired Re188 isotope. The length of the radioactive source is up to 50 mm. In this specification and claims, the expression xe2x80x9cin situxe2x80x9d indicates phenomena that take place in the therapeutic device itself The generation of Re188, in this invention, takes place in the therapeutic device itself -in situ -in contrast to the prior art.
Thus, in a preferred embodiment, the present invention provides a therapeutic device comprising a source wire having a W188/Re188 source.
For coronary brachytherapy, the outer diameter of the radioactive source should be less than 0.8 mm in order to enable insertion via small coronary vessels. Further, the inner diameter of the radioactive source should not be less than 0.36 mm.
The radioactive W188/Re188 source is preferably encapsulated inside a polymeric tube and sealed. The polymeric tube may be sealed at both ends with sealant glue. To enable use of the source for several weeks without leak or contamination problems, both in storage and in use, the polymeric material should be resistant to a more than 100 mega-rad dose. Polyimides are satisfactory materials. Other satisfactory polymers are PVDF-polyvinylidenefluoride (Kynar), PI-polyimide and silicone rubber.
Another aspect of the invention is a method of practicing radiotherapy by the use of Rhenium188 as the source of radioactivity, which comprises making a therapeutic device, as hereinbefore defined, by providing a source made of or coated with Tungsten and irradiating it, whereby to produce a radioactive solid source, allowing either undesirable short-lived gamma isotopes to decay or long-lived low-medium energy beta tungsten isotopes to be self-absorbed, introducing said source into or adjacent to the organ of the patient""s body to be treated, and allowing Rhenium188 to be generated in situ from the, irradiated Tungsten and to irradiate said organ by xcex2-emission.